TY - JOUR
T1 - Trafficking of major histocompatibility complex class II molecules in human B-lymphoblasts deficient in the AP-3 adaptor complex
AU - Caplan, Steve
AU - Dell'Angelica, Esteban C.
AU - Gahl, William A.
AU - Bonifacino, Juan S.
PY - 2000/5/1
Y1 - 2000/5/1
N2 - The major histocompatibility complex class II subunits (MHC-II) α and β assemble with the invariant chain (Ii) in the endoplasmic reticulum and are transported to endosomal-lysosomal organelles known as MHC class II compartments (MIICs). Although it has been shown that two dileucine-based signals in the cytosolic tail of Ii, as well as a dileucine-based signal in the tail of the β chain mediate sorting to MIICs, the molecular mechanisms by which αβIi complexes are sorted have yet to be resolved fully. The AP-3 adaptor complex stands out as a particularly good candidate for mediating this targeting because: (i) it has a proven role in the trafficking of membrane proteins to lysosome-related organelles; and (ii) it has the ability to interact with dileucine-based signals in vitro. To investigate the potential role of AP-3 in transport of MHC-II to MIICs, we have examined MHC- II trafficking in human B-lymphoblast lines from patients with Hermansky- Pudlak syndrome type 2 (HPS-2), which are deficient in the AP-3 complex. Pulse-chase analyses revealed no significant alteration in the kinetics of synthesis and degradation of either MHC-II subunits or Ii. Moreover, we observed neither impairment of the formation of compact SDS-resistant αβ dimers, nor delay in the appearance of a conformational epitope indicative of a mature, Ii-free αβ dimer. Finally, we demonstrated that in HPS-2 patients' cells, there was no delay in the expression of the αβ dimers on the cell surface. Thus, AP-3 does not seem to be essential for normal trafficking of MHC-II. These findings have important implications for HPS-2 patients, because they suggest that the recurrent bacterial infections suffered by these patients are not likely due to impaired antigen processing and presentation by MHC-II. (C) 2000 Published by Elsevier Science B.V.
AB - The major histocompatibility complex class II subunits (MHC-II) α and β assemble with the invariant chain (Ii) in the endoplasmic reticulum and are transported to endosomal-lysosomal organelles known as MHC class II compartments (MIICs). Although it has been shown that two dileucine-based signals in the cytosolic tail of Ii, as well as a dileucine-based signal in the tail of the β chain mediate sorting to MIICs, the molecular mechanisms by which αβIi complexes are sorted have yet to be resolved fully. The AP-3 adaptor complex stands out as a particularly good candidate for mediating this targeting because: (i) it has a proven role in the trafficking of membrane proteins to lysosome-related organelles; and (ii) it has the ability to interact with dileucine-based signals in vitro. To investigate the potential role of AP-3 in transport of MHC-II to MIICs, we have examined MHC- II trafficking in human B-lymphoblast lines from patients with Hermansky- Pudlak syndrome type 2 (HPS-2), which are deficient in the AP-3 complex. Pulse-chase analyses revealed no significant alteration in the kinetics of synthesis and degradation of either MHC-II subunits or Ii. Moreover, we observed neither impairment of the formation of compact SDS-resistant αβ dimers, nor delay in the appearance of a conformational epitope indicative of a mature, Ii-free αβ dimer. Finally, we demonstrated that in HPS-2 patients' cells, there was no delay in the expression of the αβ dimers on the cell surface. Thus, AP-3 does not seem to be essential for normal trafficking of MHC-II. These findings have important implications for HPS-2 patients, because they suggest that the recurrent bacterial infections suffered by these patients are not likely due to impaired antigen processing and presentation by MHC-II. (C) 2000 Published by Elsevier Science B.V.
KW - Antigen-processing
KW - Dileucine-based signals
KW - Hermansky-Pudlak syndrome
KW - Invariant chain
KW - Lysosomes
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U2 - 10.1016/S0165-2478(00)00176-0
DO - 10.1016/S0165-2478(00)00176-0
M3 - Article
C2 - 10841946
AN - SCOPUS:0034192934
SN - 0165-2478
VL - 72
SP - 113
EP - 117
JO - Immunology Letters
JF - Immunology Letters
IS - 2
ER -